Use of SGLT-2 inhibitors in the drying-off of non-human mammals

ABSTRACT

The present invention is directed to the use of at least one SGLT-2 inhibitor in a non-human mammal, preferably ruminant, preferably for drying-off of a non-human mammal, preferably ruminant, as well as corresponding methods, such as improving and/or facilitating the drying-off of a non-human mammal, preferably ruminant, comprising administering to such non-human mammal, preferably ruminant, at least one SGLT-2 inhibitor.

FIELD OF THE INVENTION

The invention relates to the field of medicine, in particular to thefield of veterinary medicine. The invention relates to the use of one ormore SGLT-2 inhibitors or a pharmaceutically acceptable form thereof inthe drying-off of a non-human mammal, preferably ruminants, morepreferably a ruminant.

BACKGROUND INFORMATION

In dairy cows, the duration of lactation is usually approximately 10months. After this period of lactation, milking of the animal is oftenstopped abruptly, the backpressure of milk accumulating in the udderbeing an important stimulate for involution of mammary cells to stopproducing milk. The start of the dry period is a challenge for thehealth of ruminants. Udder engorgement and pain after drying off and/ormilk leakage potentially leading to intra-mammary microbial infectionsand mastitis is a thread especially in dairy cattle with high milkyield. For every 5 kg of milk yield over 12.5 kg at dry-off, the odds ofan intra-mammary infection is increased by at least 77%.

As in other species, the sodium glucose linked transporter number 2(SGLT-2) is predominantly expressed in the bovine kidney. However, it isexpressed at lower levels in the bovine mammary gland, liver, lung,spleen, intestine, and skeletal muscle. The expression of SGLT-2 in thebovine mammary gland is increased more than 10-fold from late pregnancyto early lactation (Zhao F Q et al., J. Dairy Sci., 2005, 88:2738-2748). However, the physiological roles of the SGLTs in the mammarygland remain to be studied (Zhao F Q, J Mammary Gland Biol Neoplasia2014, 19: 3-7).

The current state of the art is “good management”—i.e.progressive/gradual cessation of milking, and/or feed reduction. Theseprocedures need several days to yield effects and, therefore, most oftenthese management tools are not implemented because of convenience, butdairy cow are subject to a sudden, abrupt dry-off.

Besides, these good management procedures have clear drawbacks. Thegradual cessation of milking does increase the somatic cell count, i.e.there is eventual commercial penalties to the milk price achieved.Intermitted udder engorgement also clearly induces discomfort andstress. There are controversies about the effects on milk leakage and/orincidence of intra-mammary infections. Similarly, feed restrictioninduces stress and discomfort. Moreover, controversial reports areavailable of effects on milk leakage and, consequently, the risk forintra-mammary infections. More important, feed restriction as needed forseveral days to effectively reduce the milk production clearly induces anegative energy balance. If this persists over several days, theincrease in blood non-esterified fatty acids (NEFAs) and ketone bodiesmay even induce “fatty liver syndrome” and/or impair the general immunestatus. In addition, to what is described above also abrupt dry-off andpainful udder engorgement also induces stress and stress is known toincrease the susceptibility of animals to infections and, thus, adds onto the risk intra-mammary infections at start of the dry period. Thus,cows at dry-off are prone for mastitis/metritis. For instance, alsosubclinical mastitis or sub-clinical ketosis are often unrecognized butmay have negative effects even on long term—i.e. the subsequentreproduction cycle/fertility and milk yield and/or milk quality.

Drugs with prolactin inhibitory effects like cabergoline may be used.Cabergoline is a synthetic ergot derivative, which is a potent dopaminereceptor agonist on D2 receptors. It acts on dopamine receptors ofprolactin producing cells in the pituitary gland suppressing theprolactin production. Consequently, cabergoline administration induces areduction of milk production leading to a reduction in udder engorgementand intra-mammary pressure at dry-off. Cabergoline is registered in somecountries for use in dairy cows as an aid in the abrupt drying-off byreducing milk production to reduce milk leakage at drying off, reducethe risk of new intra-mammary infections (IMI) during the dry period andreduce discomfort. However, the marketing authorizations for cabergolinein the EU were suspended in 2016 due to serious adverse effects,including the death of several cows.

Further prior art is as follows:

-   Bertulat S et al., (J Dairy Sci 2017, 100(4): 3220-3232) describe    the effect of a single injection of cabergoline at dry-off on udder    characteristics in high-yielding dairy cows.-   EP 2 349 272 B1 relates to a veterinary composition comprising    cabergoline for a use to induce lactation depletion and promoting    mammary involution in gestating ruminants.-   EP 2 675 527 B1 relates to the use of a veterinary composition    comprising cabergoline to be administered to a ruminant in a    specific dosage regimen.-   Gross J J et al. (J Anim Physiol Anim Nutr 2015, 99: 747-756)    disclose the glucose transport and milk secretion during manipulated    plasma insulin and glucose concentrations and during LPS-induced    mastitis in dairy cows.-   Lanctôt S et al. (J Dairy Sci 2017, 100(3): 2269-2281) describes the    effect of intra-mammary infusion of chitosan hydrogels at drying-off    on bovine mammary gland involution.-   Maynou G et al. (J Dairy Sci 2018, 101(12): 1-12) describe the    effects of oral administration of acidogenic boluses at dry-off on    performance and behavior of dairy cattle.-   US 2004/0258778 A1 relates to lactation cessation and breast    engorgement compositions based on cabbage extract and methods of use    thereof.-   US 2011/0245261 A1 relates to an antiprolactinic veterinary    composition to be administered to ruminants.-   US 2014/0024670 A1 relates to a veterinary anti-prolactin    composition to be administered to ruminants.-   U.S. Pat. No. 4,412,993 A describes methods of treating    pseudopregnancy, galactorrhea and mastitis in mammals, in particular    the dog.-   U.S. Pat. No. 6,391,849 B1 relates to a method and pharmaceutical    composition for disrupting lactation in a mammary gland and for    treating and preventing mastitis.-   U.S. Pat. No. 8,133,916 B1 relates to the control of milk production    and mammary involution.-   U.S. Pat. No. 9,487,557 B2 describes novel short peptides that are    highly effective in inducing involution in a mammary gland of a    lactating mammal and cessation of milk production by the gland.-   U.S. Pat. No. 9,744,158 B2 describes an antiprolactinic veterinary    composition to be administered to ruminants.-   WO 2004/113378 A2 relates to three novel peptides identified from    cow's milk for use in the modulation of the milk secretion rate of a    lactating cell.-   WO 2009/143020 A1 discloses methods for treating hyperuricemia    employing an SGLT-2 inhibitor alone or in combination with a supply    of carbohydrate and/or in combination with an inhibitor of uric acid    synthesis.-   WO 2015/173584 A1 discloses methods for avoiding an increase in    glucagon associated with the administration of an SGLT-2 inhibitor    via the co-administration of a DPP-IV inhibitor.-   WO 2016/104643 A1 discloses solid preparations for treating    diabetes.-   WO 2017/156632 A1 describes a method of preventing intra-mammary    infection and accelerating involution by administration of a    biological response modifier, specifically a chitosan solution to    the teat of a lactating mammal at drying-off.

Thus, there is a medical need for a safe, convenient and effective aidto reduce the risks for animal/udder/mammary gland health and increaseanimal welfare with a management of sudden dry-off in non-human mammals,preferably ruminants, which overcomes the problems of the prior art.

SUMMARY OF THE INVENTION

The present invention concerns the use of at least one SGLT-2 inhibitorin a non-human mammal, preferably ruminants, more preferably a ruminant,even more preferably for drying-off of a non-human mammal, even morepreferably ruminants, most preferably a ruminant.

A corresponding method of drying-off of a non-human mammal, preferablyruminants, more preferably a ruminant, comprising administering at leastone SGLT-2 inhibitor, a corresponding at least one SGLT-2 inhibitor foruse in a method of drying-off of a non-human mammal, preferablyruminants, more preferably a ruminant, as well as the corresponding useof at least one SGLT-2 inhibitor for the preparation of a medicament fordrying-off of a non-human mammal, preferably ruminants, more preferablya ruminant, are also intended to be comprised by the present invention.

The present invention also concerns a method of improving and/orfacilitating the drying-off of a non-human mammal, preferably ruminants,more preferably a ruminant, comprising administering to such a non-humanmammal, preferably ruminant(s) at least one SGLT-2 inhibitor.

A corresponding use of at least one SGLT-2 inhibitor, wherein such atleast one SGLT-2 inhibitor is administered to a non-human mammal,preferably ruminants, more preferably a ruminant, a corresponding atleast one SGLT-2 inhibitor for use in a method of improving and/orfacilitating the drying-off of a non-human mammal, preferably ruminants,more preferably a ruminant, wherein such at least one SGLT-2 inhibitoris administered to a non-human mammal, preferably ruminants, morepreferably a ruminant, as well as the corresponding use of at least oneSGLT-2 inhibitor for the preparation of a medicament for improvingand/or facilitating the drying-off of a non-human mammal, preferablyruminants, more preferably a ruminant, wherein such at least one SGLT-2inhibitor is administered to a non-human mammal, preferably ruminants,more preferably a ruminant, are also intended to be comprised by thepresent invention.

The present invention also concerns a method of reducing the milkproduction, preferably milk production and/or secretion, in a pregnantand/or a lactating non-human mammal, preferably ruminants, morepreferably a pregnant and/or lactating ruminant, comprisingadministering to such non-human mammal, preferably ruminant(s), at leastone SGLT-2 inhibitor.

A corresponding use of at least one SGLT-2 inhibitor, wherein such atleast one SGLT-2 inhibitor is administered to a non-human mammal,preferably ruminants, more preferably a ruminant, a corresponding atleast one SGLT-2 inhibitor for use in a method of reducing the milkproduction, preferably milk production and/or secretion, in a pregnantand/or a lactating non-human mammals, preferably ruminants, morepreferably a pregnant and/or lactating ruminant, wherein such at leastone SGLT-2 inhibitor is administered to a non-human mammal, preferablyruminants, more preferably a ruminant, as well as the corresponding useof at least one SGLT-2 inhibitor for the preparation of a medicament forreducing the milk production, preferably milk production and/orsecretion, in a pregnant and/or a lactating non-human mammal, preferablyruminants, more preferably a pregnant and/or lactating ruminant, whereinsuch at least one SGLT-2 inhibitor is administered to a non-humanmammal, preferably ruminants, more preferably a ruminant, are alsointended to be comprised by the present invention.

The present invention also concerns a method of decreasing milkaccumulation and/or engorgement in the udder, preferably udder and/ormammary gland, of a non-human mammal, preferably ruminants, morepreferably a ruminant, comprising administering to such non-humanmammal, preferably ruminant(s) at least one SGLT-2 inhibitor.

A corresponding use of at least one SGLT-2 inhibitor, wherein such atleast one SGLT-2 inhibitor is administered to a non-human mammal,preferably ruminants, more preferably a ruminant, a corresponding atleast one SGLT-2 inhibitor for use in a method of decreasing milkaccumulation and/or engorgement in the udder, preferably udder and/ormammary gland, of a non-human mammal, preferably ruminants, morepreferably a ruminant, wherein such at least one SGLT-2 inhibitor isadministered to a non-human mammal, preferably ruminants, morepreferably a ruminant, as well as the corresponding use of at least oneSGLT-2 inhibitor for the preparation of a medicament for decreasing milkaccumulation and/or engorgement in the udder, preferably udder and/ormammary gland, of a non-human mammal, preferably ruminants, morepreferably a ruminant, wherein such at least one SGLT-2 inhibitor isadministered to a non-human mammal, preferably ruminants, morepreferably a ruminant, are also intended to be comprised by the presentinvention.

The present invention also concerns a method of decreasing thediscomfort associated with udder engorgement, such as increasing thedaily lying time and/or reduction of stress, of a non-human mammal,preferably ruminants, more preferably a ruminant, comprisingadministering to such non-human mammal, preferably ruminant(s) at leastone SGLT-2 inhibitor.

A corresponding use of at least one SGLT-2 inhibitor, wherein such atleast one SGLT-2 inhibitor is administered to a non-human mammal,preferably ruminants, more preferably a ruminant, a corresponding atleast one SGLT-2 inhibitor for use in a method of decreasing thediscomfort associated with udder engorgement, such as increasing thedaily lying time and/or reduction of stress, of a non-human mammal,preferably ruminants, more preferably a ruminant, wherein such at leastone SGLT-2 inhibitor is administered to a non-human mammal, preferablyruminants, more preferably a ruminant, as well as the corresponding useof at least one SGLT-2 inhibitor for the preparation of a medicament fordecreasing the discomfort associated with udder engorgement, such asincreasing the daily lying time and/or reduction of stress, of anon-human mammal, preferably ruminants, more preferably a ruminant,wherein such at least one SGLT-2 inhibitor is administered to anon-human mammal, preferably ruminants, more preferably a ruminant, arealso intended to be comprised by the present invention.

The present invention also concerns a method of decreasing milk leakageafter drying-off of a non-human mammal, preferably ruminants, morepreferably a ruminant, comprising administering to such non-humanmammal, preferably ruminant(s) at least one SGLT-2 inhibitor.

A corresponding use of at least one SGLT-2 inhibitor, wherein such atleast one SGLT-2 inhibitor is administered to a non-human mammal,preferably ruminants, more preferably a ruminant, a corresponding atleast one SGLT-2 inhibitor for use in a method of decreasing milkleakage after drying-off of a non-human mammal, preferably ruminants,more preferably a ruminant, wherein such at least one SGLT-2 inhibitoris administered to a non-human mammal, preferably ruminants, morepreferably a ruminant, as well as the corresponding use of at least oneSGLT-2 inhibitor for the preparation of a medicament for decreasing milkleakage after drying-off of a non-human mammal, preferably ruminants,more preferably a ruminant, wherein such at least one SGLT-2 inhibitoris administered to a non-human mammal, preferably ruminants, morepreferably a ruminant, are also intended to be comprised by the presentinvention.

The present invention also concerns a method of decreasing the incidenceof intra-mammary infections (IMI), preferably mastitis and/or metritis,in a non-human mammal, preferably ruminants, more preferably a ruminant,comprising administering to such non-human mammal, preferablyruminant(s) at least one SGLT-2 inhibitor.

A corresponding use of at least one SGLT-2 inhibitor, wherein such atleast one SGLT-2 inhibitor is administered to a non-human mammal,preferably ruminants, more preferably a ruminant, a corresponding atleast one SGLT-2 inhibitor for use in a method of decreasing theincidence of intra-mammary infections (IMI), preferably mastitis and/ormetritis, in a non-human mammal, preferably ruminants, more preferably aruminant, wherein such at least one SGLT-2 inhibitor is administered toa non-human mammal, preferably ruminants, more preferably a ruminant, aswell as the corresponding use of at least one SGLT-2 inhibitor for thepreparation of a medicament for decreasing the incidence ofintra-mammary infections (IMI), preferably mastitis and/or metritis, ina non-human mammal, preferably ruminants, more preferably a ruminant,wherein such at least one SGLT-2 inhibitor is administered to anon-human mammal, preferably ruminants, more preferably a ruminant, arealso intended to be comprised by the present invention.

In one aspect, the present invention also concerns the use or methods asherein disclosed and/or claimed, wherein the at least one SGLT-2inhibitor is administered in a therapeutically effective amount withoutexerting any harmful and/or abortifacient effects on a pregnantnon-human mammal, preferably ruminant(s), and/or wherein the at leastone SGLT-2 inhibitor is administered in a therapeutically effectiveamount without exerting any negative effects on the subsequentreproduction cycle/fertility and milk yield and/or milk quality in thenext lactation.

In one aspect, the present invention also concerns the use or methods asherein disclosed and/or claimed, wherein the at least one SGLT-2inhibitor is administered in a therapeutically effective amount thatadditionally or alternatively effects a reduction of the incidence ofnew intra-mammary infections (IMI) or mastitis in the first month afterstart of the next lactation.

In one aspect, the present invention also concerns the use or methods asherein disclosed and/or claimed, wherein the at least one SGLT-2inhibitor is selected from the group consisting of:

-   -   (1) a glucopyranosyl-substituted benzene derivative of the        formula (1)

-   -   wherein R¹ denotes cyano, Cl or methyl (most preferably cyano);        -   R² denotes H, methyl, methoxy or hydroxy (most preferably H)            and        -   R³ denotes cyclopropyl, hydrogen, fluorine, chlorine,            bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl,            sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl,            cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl,            1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl,            1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl,            trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl,            hydroxymethyl, 3-hydroxy-propyl,            2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl,            1-hydroxy-1-methyl-ethyl,            2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl,            2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl,            2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy,            trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl,            methylsulfinyl, methlysulfonyl, ethylsulfinyl,            ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy            or (S)-tetrahydrofuran-3-yloxy or cyano;        -   wherein R³ is preferably selected from cyclopropyl, ethyl,            ethinyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or            (S)-tetrahydrofuran-3-yloxy; and most preferably R³ is            cyclopropyl,        -   or a derivative thereof wherein one or more hydroxyl groups            of the β-D-glucopyranosyl group are acylated with groups            selected from (C₁₋₁₈-alkyl)carbonyl,            (C₁₋₁₈-alkyl)oxycarbonyl, phenylcarbonyl and            phenyl-(C₁₋₃-alkyl)-carbonyl;    -   (2) Velagliflozin, represented by formula (2):

-   -   (3) Dapagliflozin, represented by formula (3):

-   -   (4) Canagliflozin, represented by formula (4):

-   -   (5) Empagliflozin, represented by formula (5):

-   -   (6) Luseogliflozin, represented by formula (6):

-   -   (7) Tofogliflozin, represented by formula (7):

-   -   (8) Ipragliflozin, represented by formula (8):

-   -   (9) Ertugliflozin, represented by formula (9):

-   -   (10) Atigliflozin, represented by formula (10):

-   -   (11) Remogliflozin, represented by formula (11):

-   -   (11A) Remogliflozin etabonate, represented by formula (11A):

-   -   (12) a thiophene derivative of the formula (12)

-   -   wherein R denotes methoxy or trifluoromethoxy;    -   (13)        1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene,        represented by formula (13);

-   -   (14) a spiroketal derivative of the formula (14):

-   -   wherein R denotes methoxy, trifluoromethoxy, ethoxy, ethyl,        isopropyl or tert. butyl;    -   (15) a pyrazole-O-glucoside derivative of the formula (15)

-   -   wherein        -   R¹ denotes C₁₋-alkoxy,        -   L¹, L² independently of each other denote H or F,        -   R⁶ denotes H, (C₁₋₃-alkyl)carbonyl, (C₁₋₆-alkyl)oxycarbonyl,            phenyloxycarbonyl, benzyloxycarbonyl or benzylcarbonyl;    -   (16) Sotagliflozin, represented by formula (16):

-   -   (17) Sergliflozin, represented by formula (17):

-   -   (18) a compound represented by formula (18):

-   -   wherein        -   R³ denotes cyclopropyl, hydrogen, fluorine, chlorine,            bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl,            sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl,            cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl,            1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl,            1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl,            trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl,            hydroxymethyl, 3-hydroxy-propyl,            2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl,            1-hydroxy-1-methyl-ethyl,            2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl,            2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl,            2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy,            trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl,            methylsulfinyl, methlysulfonyl, ethylsulfinyl,            ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy            or (S)-tetrahydrofuran-3-yloxy or cyano, wherein R³ is            preferably selected from cyclopropyl, ethyl, ethinyl,            ethoxy, (R)-tetrahydrofuran-3-yloxy or            (S)-tetrahydrofuran-3-yloxy; and R³ most preferably is            cyclopropyl,        -   or a derivative thereof wherein one or more hydroxyl groups            of the β-D-glucopyranosyl group are acylated with groups            selected from (C₁₋₁₈-alkyl)carbonyl,            (C₁₋₁₈-alkyl)oxycarbonyl, phenylcarbonyl and            phenyl-(C₁₋₃-alkyl)-carbonyl;    -   (19) Bexagliflozin, represented by formula (19):

-   -   (20) Janagliflozin, represented by formula (20):

-   -   (21) Rongliflozin,    -   (22) Wanpagliflozin.

In one aspect, the present invention also concerns the use or methods asherein disclosed and/or claimed, wherein the non-human mammal,preferably ruminant(s), is/are selected from the group consisting of:bovine, canine, caprine, equine, feline, lagomorphs, ovine, porcine,rodent; preferably selected from the group consisting of: cattle, cow,dog, goat, horse, pony, donkey, cat, sheep, pig, rabbit, rat, mouse;more preferably selected from the group consisting of bovine, caprine,ovine, even more preferably selected from the group consisting of:cattle, cow(s), goat(s), sheep; even more preferably selected from thegroup consisting of: dairy cattle, pregnant and/or lactating dairycattle; most preferably selected from the group consisting of: cow(s),pregnant and/or lactating cow(s).

In one aspect, the present invention also concerns the use or methods asherein disclosed and/or claimed, wherein the at least one SGLT-2inhibitor is administered orally, parenterally, rectally,intravaginally, intravenously, subcutaneously or intramuscularly,preferably subcutaneously, intramuscularly or intravenously.

In one aspect, the present invention also concerns the use or methods asherein disclosed and/or claimed, wherein the at least one SGLT-2inhibitor is administered at a dose of 0.01 mg/kg bodyweight to 10 mg/kgbodyweight, preferably at a dose of 0.01 mg/kg bodyweight to 5 mg/kgbodyweight, more preferably at a dose of 0.01 mg/kg bodyweight to 3mg/kg bodyweight, even more preferably at a dose of 0.03 mg/kgbodyweight to 3 mg/kg bodyweight, most preferably at a dose of 0.03mg/kg bodyweight or 0.3 mg/kg bodyweight or 3 mg/kg bodyweight.

In one aspect, the present invention also concerns the use or methods asherein disclosed and/or claimed, wherein the at least one SGLT-2inhibitor is administered once, twice, three-times, four-times,five-times, six-times or daily for a week, preferably once only at startof drying-off or twice as two treatments 24 hours or 48 hours apartafter last milking.

In one aspect, the present invention also concerns the use or methods asherein disclosed and/or claimed, wherein the at least one SGLT-2inhibitor is velagliflozin and velagliflozin is administered as singleSGLT-2 inhibitor, preferably orally, subcutaneously or intramuscularly,once only at start of drying-off or twice (24 h or 48 h apart) at a doseof 0.01 mg/kg bodyweight to 5 mg/kg bodyweight, more preferably 0.03mg/kg bodyweight to 3 mg/kg bodyweight, even more preferably at a doseof 0.03 mg/kg bodyweight or 0.3 mg/kg bodyweight or 3 mg/kg bodyweight.

In one aspect, the present invention also concerns the use or methods asherein disclosed and/or claimed, wherein the at least one SGLT-2inhibitor is administered before, after or concomitantly withadministering at least one feed supplement, such as Bovikalc® Dry, tothe non-human mammal, preferably ruminant(s), and/or before, after orconcomitantly with a reduction in feed offered to the non-human mammal,preferably ruminant(s).

In one aspect, the present invention also concerns the use or methods asherein disclosed and/or claimed, wherein the feed supplement comprisesone or more acidifying agents selected from the group consisting of:ammonium chloride, calcium chloride and/or calcium sulfate, morepreferably comprises ammonium chloride and calcium chloride and calciumsulfate, even more preferably comprises 5% (w/w) to 15% (w/w) ammoniumchloride and 40% (w/w) to 60% (w/w) calcium chloride and 15% (w/w) to25% (w/w) calcium sulfate, most preferably comprises 10.4% (w/w)ammonium chloride and 51.9% (w/w) calcium chloride and 20.1% (w/w)calcium sulfate.

The advantages according to the present invention are one or more of thefollowing:

-   -   facilitates the start of the dry period at the end of lactation        in a non-human mammal, preferably ruminant, with a safe,        effective and convenient parenteral injection of at least one        SGLT2 inhibitor;    -   overcomes the problems that even good management procedures have        drawbacks, such as an increase of the somatic cell counts while        still delivering milk in gradual cessation of milking prior to        dry-off;    -   ameliorates discomfort and stress related good management as        well as abrupt dry-off, which is known to impact the immune        status negatively;    -   increases the daily lying time and reduces stress, preferably on        the days after dry-off,    -   improves the immune status and/or liver function of a non-human        mammal, preferably ruminant, more preferably dairy cow(s), after        dry-off;    -   avoids scenarios like feed reduction induced negative energy        balance with eventually excessive increase in blood        non-esterified fatty acids (NEFAs) and ketone bodies that may        even induce “fatty liver syndrome” and/or impair the general        immune status;    -   advantageously influences the long-time performance of a        non-human mammal, preferably ruminant, by avoiding the negative        impact on subsequent reproduction cycle/fertility and milk yield        and/or milk quality in the next lactation.

DETAILED DESCRIPTION OF THE INVENTION

Before the embodiments of the present invention are described in furtherdetail, it shall be noted that as used herein and in the appendedclaims, the singular forms “a”, “an”, and “the” include plural referenceunless the context clearly dictates otherwise.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art to which this invention belongs. All given ranges and valuesmay vary by 1 to 5% unless indicated otherwise or known otherwise by theperson skilled in the art, therefore, the term “about” was usuallyomitted from the description and claims. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the preferred methods,devices, and materials are now described. All publications mentionedherein are incorporated herein by reference for the purpose ofdescribing and disclosing the substances, excipients, carriers, andmethodologies as reported in the publications which might be used inconnection with the invention. Nothing herein is to be construed as anadmission that the invention is not entitled to antedate such disclosureby virtue of prior invention.

In the course of the present invention, “drying-off” is defined asfollows: cessation of milking, preferably milk secretion, of a lactatingnon-human mammal, preferably ruminant.

In the course of the present invention “improving and/or facilitatingthe drying-off” is defined as follows: faster reduction of milkproduction, preferably milk secretion.

In the course of the present invention the term “mastitis” refers to theinflammation of the mammary gland caused by intra-mammary infection(IMI) with pathogens, mostly bacteria, but also yeast, fungi, or evenalgae. “Mastitis” is herein used to describe all forms of suchinflammation, including subclinical and clinical mastitis, clinicalmastitis including mild, severe and chronic mastitis.

In the course of the present invention the term “udder engorgement” or“engorgement in the udder” refers to the excessive accumulation of milkin the mammary gland, leading to pain and discomfort and/or milk leakagefrom the teats; also interchangeably, the term increased udder pressureis used.

In the course of the present invention the term “treatment effects”refers to an improvement and/or reduction of a condition or incidence,and/or the improvement, reduction or increase of any effect, index,marker level or other parameter relating to a condition. SGLT-2inhibitors for use according to the invention include, but are notlimited to, glucopyranosyl-substituted benzene derivatives, for exampleas described in WO 01/27128, WO 03/099836, WO 2005/092877, WO2006/034489, WO 2006/064033, WO 2006/117359, WO 2006/117360, WO2007/025943, WO 2007/028814, WO 2007/031548, WO 2007/093610, WO2007/128749, WO 2008/049923, WO 2008/055870, WO 2008/055940, WO2009/022020 or WO 2009/022008.

Moreover, the one or more SGLT-2 inhibitors for use according to theinvention may be selected from the group consisting of the followingcompounds or pharmaceutically acceptable forms thereof:

-   -   (1) a glucopyranosyl-substituted benzene derivative of the        formula (1)

-   -   wherein R¹ denotes cyano, Cl or methyl (most preferably cyano);        -   R² denotes H, methyl, methoxy or hydroxy (most preferably H)            and        -   R³ denotes cyclopropyl, hydrogen, fluorine, chlorine,            bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl,            sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl,            cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl,            1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl,            1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl,            trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl,            hydroxymethyl, 3-hydroxy-propyl,            2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl,            1-hydroxy-1-methyl-ethyl,            2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl,            2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl,            2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy,            trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl,            methylsulfinyl, methlysulfonyl, ethylsulfinyl,            ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy            or (S)-tetrahydrofuran-3-yloxy or cyano;        -   wherein R³ is preferably selected from cyclopropyl, ethyl,            ethinyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or            (S)-tetrahydrofuran-3-yloxy; and most preferably R³ is            cyclopropyl,        -   or a derivative thereof wherein one or more hydroxyl groups            of the β-D-glucopyranosyl group are acylated with groups            selected from (C₁₋₁₈-alkyl)carbonyl,            (C₁₋₁₈-alkyl)oxycarbonyl, phenylcarbonyl and            phenyl-(C₁₋₃-alkyl)-carbonyl;    -   (2) Velagliflozin, represented by formula (2):

-   -   (3) Dapagliflozin, represented by formula (3):

-   -   (4) Canagliflozin, represented by formula (4):

-   -   (5) Empagliflozin, represented by formula (5):

-   -   (6) Luseogliflozin, represented by formula (6):

-   -   (7) Tofogliflozin, represented by formula (7):

-   -   (8) Ipragliflozin, represented by formula (8):

-   -   (9) Ertugliflozin, represented by formula (9):

-   -   (10) Atigliflozin, represented by formula (10):

-   -   (11) Remogliflozin, represented by formula (11):

-   -   (11A) Remogliflozin etabonate, represented by formula (11A):

-   -   (12) a thiophene derivative of the formula (12)

-   -   wherein R denotes methoxy or trifluoromethoxy;    -   (13)        1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene,        represented by formula (13);

-   -   (14) a spiroketal derivative of the formula (14):

-   -   wherein R denotes methoxy, trifluoromethoxy, ethoxy, ethyl,        isopropyl or tert. butyl;    -   (15) a pyrazole-O-glucoside derivative of the formula (15)

-   -   wherein        -   R¹ denotes C₁₋-alkoxy,        -   L¹, L² independently of each other denote H or F,        -   R⁶ denotes H, (C₁₋₃-alkyl)carbonyl, (C₁₋₆-alkyl)oxycarbonyl,            phenyloxycarbonyl, benzyloxycarbonyl or benzylcarbonyl;    -   (16) Sotagliflozin, represented by formula (16):

-   -   (17) Sergliflozin, represented by formula (17):

-   -   (18) a compound represented by formula (18):

-   -   wherein        -   R³ denotes cyclopropyl, hydrogen, fluorine, chlorine,            bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl,            sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl,            cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl,            1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl,            1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl,            trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl,            hydroxymethyl, 3-hydroxy-propyl,            2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl,            1-hydroxy-1-methyl-ethyl,            2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl,            2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl,            2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy,            trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl,            methylsulfinyl, methlysulfonyl, ethylsulfinyl,            ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy            or (S)-tetrahydrofuran-3-yloxy or cyano; and wherein R³ is            preferably selected from cyclopropyl, ethyl, ethinyl,            ethoxy, (R)-tetrahydrofuran-3-yloxy or            (S)-tetrahydrofuran-3-yloxy; and R³ most preferably is            cyclopropyl,        -   or a derivative thereof wherein one or more hydroxyl groups            of the β-D-glucopyranosyl group are acylated with groups            selected from (C₁₋₁₈-alkyl)carbonyl,            (C₁₋₁₈-alkyl)oxycarbonyl, phenylcarbonyl and            phenyl-(C₁₋₃-alkyl)-carbonyl;    -   (19) Bexagliflozin, represented by formula (19):

-   -   (20) Janagliflozin, represented by formula (20):

-   -   (21) Rongliflozin,    -   (22) Wanpagliflozin.

The term “velagliflozin” as employed herein refers to velagliflozin ofthe above structure as well as pharmaceutically acceptable formsthereof, including hydrates and solvates thereof, and crystalline formsthereof. The compound, methods of its synthesis and co-crystals thereofare described in WO 2007/128749, WO 2014/016381 and WO 2019/121509 forexample.

The term “dapagliflozin” as employed herein refers to dapagliflozin ofthe above structure as well as pharmaceutically acceptable formsthereof, including hydrates and solvates thereof, and crystalline formsthereof. The compound and methods of its synthesis are described in WO03/099836 for example. Preferred hydrates, solvates and crystallineforms are described in the patent applications WO 2008/116179 and WO2008/002824 for example.

The term “canagliflozin” as employed herein refers to canagliflozin ofthe above structure as well as pharmaceutically acceptable formsthereof, including hydrates and solvates thereof, and crystalline formsthereof. The compound and methods of its synthesis are described in WO2005/012326 and WO 2009/035969 for example. Preferred hydrates, solvatesand crystalline forms are described in the patent application WO2008/069327 for example.

The term “empagliflozin” as employed herein refers to empagliflozin ofthe above structure as well as pharmaceutically acceptable formsthereof, including hydrates and solvates thereof, and crystalline formsthereof. The compound and methods of its synthesis are described in WO2005/092877, WO 2006/120208 and WO 2011/039108 for example. A preferredcrystalline form is described in the patent applications WO 2006/117359and WO 2011/039107 for example.

The term “atigliflozin” as employed herein refers to atigliflozin of theabove structure as well as pharmaceutically acceptable forms thereof,including hydrates and solvates thereof, and crystalline forms thereof.The compound and methods of its synthesis are described in WO2004/007517 for example.

The term “ipragliflozin” as employed herein refers to ipragliflozin ofthe above structure as well as pharmaceutically acceptable formsthereof, including hydrates and solvates thereof, and crystalline formsthereof. The compound and methods of its synthesis are described in WO2004/080990, WO 2005/012326 and WO 2007/114475 for example.

The term “tofogliflozin” as employed herein refers to tofogliflozin ofthe above structure as well as pharmaceutically acceptable formsthereof, including hydrates and solvates thereof, and crystalline formsthereof. The compound and methods of its synthesis are described in WO2007/140191 and WO 2008/013280 for example.

The term “luseogliflozin” as employed herein refers to luseogliflozin ofthe above structure as well as pharmaceutically acceptable formsthereof, including hydrates and solvates thereof, and crystalline formsthereof.

The term “ertugliflozin” as employed herein refers to ertugliflozin ofthe above structure as well as pharmaceutically acceptable formsthereof, including hydrates and solvates thereof, and crystalline formsthereof. The compound is described for example in WO 2010/023594.

The term “remogliflozin” as employed herein refers to remogliflozin ofthe above structure as well as pharmaceutically acceptable formsthereof, including prodrugs of remogliflozin, in particularremogliflozin etabonate, including hydrates and solvates thereof, andcrystalline forms thereof. Methods of its synthesis are described in thepatent applications EP 1 213 296 and EP 1 354 888 for example.

The term “sergliflozin” as employed herein refers to sergliflozin of theabove structure as well as pharmaceutically acceptable forms thereof,including prodrugs of sergliflozin, in particular sergliflozinetabonate, including hydrates and solvates thereof, and crystallineforms thereof. Methods for its manufacture are described in the patentapplications EP 1 344 780 and EP 1 489 089 for example.

The compound of formula (16) above, i.e. sotagliflozin, and itsmanufacture are described for example in WO 2008/042688 or WO2009/014970.

Preferred SGLT-2 inhibitors are glucopyranosyl-substituted benzenederivatives. Optionally, one or more hydroxyl groups of theglucopyranosyl group in such one or more SGLT-2 inhibitors may beacylated with groups selected from (C₁₋₁₈-alkyl)carbonyl,(C₁₋₁₈-alkyl)oxycarbonyl, phenylcarbonyl andphenyl-(C₁₋₃-alkyl)-carbonyl.

More preferred are glucopyranosyl-substituted benzonitrile derivativesof formula (1) as disclosed herein above. Yet more preferred areglucopyranosyl-substituted benzonitrile derivatives of formula (18):

-   -   wherein    -   R³ denotes cyclopropyl, hydrogen, fluorine, chlorine, bromine,        iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,        iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl,        cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl,        1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl,        1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl,        trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl,        hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl,        3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl,        2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl,        2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl,        2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy,        trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl,        methylsulfinyl, methlysulfonyl, ethylsulfinyl, ethylsulfonyl,        trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or        (S)-tetrahydrofuran-3-yloxy or cyano; and wherein R³ is        preferably selected from cyclopropyl, ethyl, ethinyl, ethoxy,        (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; and        R³ most preferably is cyclopropyl,    -   or a derivative thereof wherein one or more hydroxyl groups of        the β-D-glucopyranosyl group are acylated with groups selected        from (C₁₋₁₈-alkyl)carbonyl, (C₁₋₁₈-alkyl)oxycarbonyl,        phenylcarbonyl and phenyl-(C₁₋₃-alkyl)-carbonyl.

Preferably, such SGLT-2 inhibitor is velaglifozin as shown in formula(2). Optionally, one or more hydroxyl groups of the β-D-glucopyranosylgroup of velagliflozin may be acylated with groups selected from(C₁₋₁₈-alkyl)carbonyl, (C₁₋₁₈-alkyl)oxycarbonyl, phenylcarbonyl andphenyl-(C₁₋₃-alkyl)-carbonyl.

Thus, in a preferred embodiment, the at least one SGLT-2 inhibitoraccording to the present invention is a glucopyranosyl-substitutedbenzene derivative SGLT-2 inhibitor, preferably a SGLT-2 inhibitor offormula (1), more preferably of formula (18), or yet more preferably offormula (2), i.e. velagliflozin, in each case as defined herein above.

Herein, references to SGLT-2 inhibitors and/or their use according tothe invention encompass pharmaceutically acceptable forms of the SGLT-2inhibitors, unless otherwise stated. According to the invention, anypharmaceutically acceptable form of the SGLT-2 inhibitor, e.g. offormula (1), preferably formula (18), more preferably formula (2), maybe used. E.g. a crystalline form may be used. Prodrug forms are alsoencompassed by the present invention.

Prodrug forms may include, e.g., esters and/or hydrates. The term“prodrug” is also meant to include any covalently bonded carrier, whichreleases the active compound of the invention in vivo when the prodrugis administered to a mammalian subject. Prodrugs of a compound of theinvention may be prepared by modifying functional groups present in thecompound of the invention in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompound of the invention.

Crystalline forms for use according to the invention include a complexof an SGLT-2 inhibitor with one or more amino acids (see e.g. WO2014/016381)—so-called co-crystals. An amino acid for such use may be anatural amino acid. The amino acid may be a proteogenic amino acid(including L-hydroxyproline), or a non-proteogenic amino acid. The aminoacid may be a D- or an L-amino acid. In some preferred embodiments, theamino acid is proline (L-proline and/or D-proline, preferablyL-proline). E.g., a crystalline complex/co-crystal of velagliflozin withproline (e.g. L-proline) and crystalline water is preferred.

Thus, herein is disclosed a crystalline complex/co-crystal between oneor more natural amino acids and an SGLT-2 inhibitor, e.g., a crystallinecomplex/co-crystal between one or more natural amino acids and aglucopyranosyl-substituted benzene derivative SGLT-2 inhibitor,preferably a SGLT-2 inhibitor of formula (1), more preferably of formula(18) or yet more preferably of formula (2) (velagliflozin).

Furthermore, the availability of a well-defined crystalline form allowsthe purification of the drug substance by recrystallization.

Apart from the requirements indicated above, it should be generallyborne in mind that any change to the solid state of a pharmaceuticalcomposition, which is capable of improving its physical and chemicalstability, gives a significant advantage over less stable forms of thesame medicament.

A crystalline complex/co-crystal between a natural amino acid and anSGLT-2 inhibitor (e.g. a glucopyranosyl-substituted benzene derivativeor a SGLT-2 inhibitor of formula (1), or formula (18) or, particularly,of formula (2), i.e. velaglilfozin) fulfills important requirementsmentioned hereinbefore.

SGLT-2 inhibitors for use according to the invention may be prepared aspharmaceutical compositions. They may be prepared as solid or as liquidformulations. In either case, they are preferably prepared forparenteral administration, preferably in liquid form for parenteraladministration (see e.g. WO 2017/032799). The SGLT-2 inhibitors may,however, also be prepared, e.g., for oral administration. Solidformulations include tablets, granular forms, and other solid forms suchas suppositories. Among solid formulations, tablets and granular formsare preferred.

Pharmaceutical compositions within the meaning of the present inventionmay comprise an SGLT-2 inhibitor according to the present invention andone or more excipients. Any excipient that allows for, or supports, theintended medical effect may be used. Such excipients are available tothe skilled person. Useful excipients are for example anti-adherents(used to reduce the adhesion between the powder (granules) and the punchfaces and thus prevent sticking to tablet punches), binders (solutionbinders or dry binders that hold the ingredients together), coatings (toprotect tablet ingredients from deterioration by moisture in the air andmake large or unpleasant-tasting tablets easier to swallow),disintegrants (to allow the tablet to break upon dilution), fillers,diluents, flavours, colours, glidants (flow regulators—to promote powderflow by reducing interparticle friction and cohesion), lubricants (toprevent ingredients from clumping together and from sticking to thetablet punches or capsule filling machine), preservatives, sorbents,sweeteners etc.

Formulations according to the invention, e.g. solid formulations, maycomprise carriers and/or disintegrants selected from the group of sugarsand sugar alcohols, e.g. mannitol, lactose, starch, cellulose,microcrystalline cellulose and cellulose derivatives, e.g.methylcellulose, and the like.

Manufacturing procedures for formulations suitable for ruminants areknown to the person skilled in the art, and for solid formulationscomprise, e.g., direct compression, dry granulation and wet granulation.In the direct compression process, the active ingredient and all otherexcipients are placed together in a compression apparatus that isdirectly applied to press tablets out of this material. The resultingtablets can optionally be coated afterwards in order to protect themphysically and/or chemically, e.g. by a material known from the state ofthe art.

A unit for administration, e.g. a single liquid dose or a unit of asolid formulation, e.g. a tablet, may comprise 0.1 mg to 10 mg, or e.g.0.3 mg to 1 mg, 1 mg to 3 mg, 3 mg to 10 mg; or 5 to 2500 mg, or e.g. 5to 2000 mg, 5 mg to 1500 mg, 10 mg to 1500 mg, 10 mg to 1000 mg, or10-500 mg of an SGLT-2 inhibitor for use according to the invention. Asthe skilled person would understand, the content of the SGLT-2 inhibitorin a solid formulation, or any formulation as disclosed herein foradministration to a ruminant, may be increased or decreased asappropriate in proportion to the body weight of the non-human mammal,preferably ruminant, to be treated.

In one embodiment, a pharmaceutical composition for use according to theinvention is designed for oral or parenteral administration, preferablyfor parenteral administration. Especially the oral administration isameliorated by excipients, which modify the smell and/or hapticproperties of the pharmaceutical composition for the intended patient,e.g. as described.

When the SGLT-2 inhibitor for use according to the invention isformulated for oral administration, it is preferred that excipientsconfer properties, e.g. palatability and/or chewability that render theformulation suitable for administration to a non-human mammal,preferably ruminant.

Also preferred are liquid formulations. Liquid formulations may be,e.g., solutions, syrups or suspensions. They may be administereddirectly to the ruminant or may be mixed with the food and/or drink(e.g. drinking water, or the like) of the ruminant. One advantage of aliquid formulation (similar to a formulation in granular form), is thatsuch a dosage form allows precise dosing. For example, the SGLT-2inhibitor may be dosed precisely in proportion to the body mass of anon-human mammal, preferably ruminant. Typical compositions of liquidformulations are known to the person skilled in the art.

A practitioner skilled in the art can determine suitable doses for theuses of the present invention. Preferred units dosing units includemg/kg bodyweight, i.e. mg SGLT-2 inhibitor per body mass of thenon-human mammal, preferably ruminant. An SGLT-2 inhibitor of thepresent invention may, e.g., be administered in doses of 0.01-10 mg/kgbodyweight per day, e.g. 0.01-5 mg/kg bodyweight per day, e.g. 0.01-4mg/kg bodyweight per day, e.g. 0.01-3 mg/kg bodyweight per day, e.g.0.01-2 mg/kg bodyweight per day, e.g. 0.01-1.5 mg/kg bodyweight per day,e.g., 0.01-1 mg/kg bodyweight per day, e.g. 0.01-0.75 mg/kg bodyweightper day, e.g. 0.01-0.5 mg/kg bodyweight per day, e.g. 0.01-0.4 mg/kgbodyweight per day; or 0.03 to 3.0 mg/kg bodyweight per day, preferablyfrom 0.02 to 2.0 mg/kg bodyweight per day, more preferably from 0.01 to1 mg/kg bodyweight per day. In another preferred embodiment, the dose is0.03 mg/kg bodyweight or 0.3 mg/kg bodyweight or 3 mg/kg bodyweight. Apractitioner skilled in the art is able to prepare an SGLT-2 inhibitorof the invention for administration according to a desired dose.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the correlation between velagliflozin plasma concentrationsand urinary glucose excretion normalized to urinary creatinine(glucose/creatinine) in Holstein-Frisian cows.

FIG. 2 depicts the delta values (kg) between mean afternoon (postmeridian—PM) milking of two days before administration of velagliflozinand milk yield (individual values) about 8 hours after i.v.administration (PM milking) of three different doses of velagliflozin(0.03 mg/kg bodyweight; 0.3 mg/kg bodyweight and 3 mg/kg bodyweight) indairy cows. It further depicts the correlation between reduction of milkyield and velagliflozin plasma concentrations 8 hours after treatment inHolstein-Frisian cows.

EXAMPLES

The following examples serve to further illustrate the presentinvention; but the same should not be construed as a limitation of thescope of the invention disclosed herein.

Example 1 Pharmacokinetics (PK)/Pharmacodynamics (PD) and Milk Reductionby a Single Velagliflozin Dosing in Lactating Cows

Velagliflozin treatment is tested in n=4 lactating Holstein-Frisiancows. In weekly intervals, velagliflozin is administered intravenously(i.v.) in increasing doses (0.03 mg/kg bodyweight-0.3 mg/kg bodyweight-3mg/kg bodyweight) in the morning after AM (ante meridian) milking intothe right jugular vein in a volume of 2.5 ml of a propylene glycol basedsolution per 100 kg body weight. Blood samples for determination ofvelagliflozin plasma levels and urine samples for determination ofglucose and creatinine levels are collected one day prior to treatmentand ˜8 hours, ˜24 hours and ˜48 hours post treatment and stored frozenuntil being analysed. Blood glucose and ketone body(beta-hydroxy-butyrate) concentrations are determined immediately afterblood collection at the same time points. The total urinary creatinineexcreted per day is rather constant in mammals, thus, since urine volumewas not determined, the glucose to creatinine ratio was calculated as asurrogate of the total glucose excretion. All animals are milked twicedaily, in the morning (ante meridian—AM) and in the late afternoon (postmeridian—PM). Throughout the study, milk yield is recorded as kg peranimal per milking.

Results:

-   -   Velagliflozin plasma level show a linear dose to exposure        relationship (see FIG. 1 ).    -   The urinary glucose excretion normalized to urinary creatinine        increases in a dose/exposure dependent manner (FIG. 1 ).    -   After treatment, the milk yield of the subsequent milking (PM)        decreases in a dose/exposure dependent manner (FIG. 2 ).    -   Of safety relevance, blood glucose or ketone body level were        within normal reference ranges after treatment with all dosages        of velagliflozin.

Clearly, these effects are dependent on the plasma velagliflozin level,indicating that also other parenteral administration routes—e.g.intramuscular or subcutaneous administrations are effective. It is thusconcluded that a single (e.g. parenteral) dose of at least one SGLT-2inhibitor, such as velagliflozin, can be safely employed in lactatingcows to reduce milk yield.

Example 2 Reduction of Milk Production and Udder Engorgement

In studies in lactating cows, SGLT-2 inhibitor, such as velaglifozin,treatment can be performed as a single parenteral administration,preferably s.c. or i.m. or also as two treatments e.g. ˜24 h or 48 hapart.

The treatment is also performed in combination with or subsequently totreatment with feed supplements, e.g. Bovikalc® Dry, and/or a reductionin feed offered to the cow with the aim to reduce the milk productionprior to dry-off.

Reduction in milk yield is evaluated by weighing of the milk yield peranimal and per milking (see e.g. Example 1).

Udder engorgement is evaluated by measuring the teat distance, by directpressure measurements and/or measuring udder firmness—indicative forengorgement using for instance a dynamometer (e.g. Penefel DFT 14; AgroTechnologies, Forges-les-Eaux, France). These readings are comparedbetween measurements before the last milking with those on the followingdays after dry-off. However, also treatment effects on reduction in milkyield and udder engorgement can be compared between cows treated with atleast one SGLT-2 inhibitor with cows that receive no treatment or cowsoffered a reduced feed ration only.

Example 3 Effects on Milk Composition and Involution Marker

In studies as described in Example 2, concurrent with the reduction inmilk yield changes in the composition of the milk/secreted fluid,indicating the involution of the secretory cells and/or the disruptionof cellular tight junctions are investigated. For instance, somatic cellcounts, bovine serum albumin, lactose, potassium and sodium as well astotal protein, whey protein, casein protein, protease peptone,lactoferrin level and/or the gelatinase activity are measured.

To achieve this, small amounts of mammary secretions (5 to 50 mL) arecollected from alternating quarters on several days after the lastmilking, i.e. dry-off.

These readings are compared with measurements before the last milkingcompared with those on the following days after dry-off; but alsotreatment effects may be compared between cows treated with at least oneSGLT-2 inhibitor, e.g. velagliflozin, with cows that receive notreatment or cows offered a reduced feed ration only.

Example 4 Reduction of Milk Leakage and Intra-Mammary Infections (IMI)During Dry Period

In studies as described in Example 2, also in the first days afterdry-off leakage of milk from the mammary gland, i.e. milk dropping orflowing from any teat is evaluated. In addition, the udder quarter canbe closely monitored to detect symptoms of intra-mammary infections ormastitis, i.e. warm or hot, sensitive or swollen udder quarters.Besides, symptoms of systemic illness, e.g. signs of fever, rapid pulse,depression, weakness and loss of appetite may be present. Also, smallamounts of mammary secretions (5 to 50 mL) are collected fromalternating quarters on several days after the last milking, i.e.dry-off to investigate eventual subclinical intra-mammaryinfections/presence of microorganisms.

These readings are compared between cows treated with at least oneSGLT-2 inhibitor, such as velagliflozin, with cows that receive notreatment or cows offered a reduced feed ration only.

Example 5 Reduction of Discomfort and Stress Caused by Dry-Off

In studies in pregnant, lactating cows, SGLT-2 inhibitor treatment, forinstance by means of velagliflozin, is installed typically e.g. in theeighth month of gestation at dry-off. The treatment is also performed incombination with or subsequently to treatment with feed supplements,e.g. Bovikalc® Dry, and/or a reduction in feed offered to the cow withthe aim to reduce the milk production prior to dry-off.

Stress and/or other discomfort measurements after dry-off are evaluatedrecording the time spent lying and/or ruminating. In addition, theincrease in the concentration of blood cortisol or faecal glucocorticoidmetabolites is measured.

An udder pain score can be employed, i.e. the behaviour of the cows maybe classified into 4 categories (0=no udder pain; 1=light udder pain;2=moderate udder pain and 3=severe udder pain) depending on theirreaction at udder palpation (from no behavioural response to refusal ofthe palpation).

These readings are compared between cows treated with at least oneSGLT-2 inhibitor, such as velagliflozin, with cows that receive notreatment or cows offered a reduced feed ration only.

Example 6 Treatment in Ruminants at Dry-Off—Safety and Long Term Effects

In studies in pregnant, lactating cows, treatment with at least oneSGLT-2 inhibitor, such as velagliflozin, can be installed typically e.g.in the eighth month of gestation at dry-off. The treatment is performedas a single administration or also as two treatments ˜24 h or 48 h apartafter last milking. The treatment is also performed in combination withor subsequently to treatment with feed supplements, e.g. Bovikalc® Dry,and/or a reduction in feed offered to the cow with the aim to reduce themilk production prior to dry-off.

The safety of a for instance velagliflozin treatment can be assessed byevaluating the metabolic response of the negative energy balanceinduced, i.e. evaluating the blood glucose and ketone body, as well asthe blood lipid concentrations (e.g. NEFAs). In addition, theelectrolyte balance of the cows is monitored, with e.g. specialemphasise on the calcium homeostasis.

The administration of at least one SGLT-2 inhibitor, such asvelagliflozin, even makes it possible to improve the immune statusand/or liver function of dairy cows. This can be measured by markers ofa systemic proinflammatory status, e.g. acute phase proteins like serumamyloid A (SAA) or haptoglobulin.

Besides, the impact on the foetus or even abortive effects can bemonitored.

Severity and incidence of safety relevant observations are comparedbetween SGLT-2 inhibitor (e.g. velagliflozin) treated cows with cowsthat receive no treatment or cows offered a reduced feed ration. Inaddition, a combined treatment with the SGLT-2 inhibitor, e.g.velagliflozin, and offering reduced feed ratios shows that there is noadverse influence of the SGLT-2 inhibitor, e.g. velagliflozin, treatmentat dry-off on the safety of a pregnant cow and the foetus.

In studies where the subsequent lactation is monitored it can be shownthat treatment with at least one SGLT-2 inhibitor, such asvelagliflozin, does not negatively affect reproduction/fertility and/ormilk yield and/or quality of milk in the next lactation. In contrast, itcan even reduce the incidence of new intra-mammary infections ormastitis in the first month after start of the next lactation.

These readings are compared between cows treated with at least oneSGLT-2 inhibitor, such as velagliflozin, with cows that receive notreatment or cows offered a reduced feed ration only prior to dry-off.

Example 7 Dose/Pharmacodynamics (PD) of Dapagliflozin after a SingleParenteral Injection in Lactating Ruminants

In studies in pregnant or non-pregnant, lactating cows, treatment withdapagliflozin is performed as described in Example 1. I.e. employing adose escalation design the cows receive a single parenteral injectioncontaining dapagliflozin in weekly intervals. Urinary glucose andcreatinine, blood glucose and ketone body concentration and milk yieldare measured. Pharmacodynamics data are evaluated as described inExample 1. Thus, it is investigated:

-   -   If the urinary glucose excretion normalized to urinary        creatinine increases in a dose/exposure dependent manner.    -   That, after treatment, the milk yield of the subsequent milking        (PM) decreases in a dose/exposure dependent manner.    -   And also, if blood glucose or ketone body level stay within        normal reference ranges after treatment with all dosages.

Thus, similar to what is described with velagliflozin, also fordapagliflozin it is anticipated that a parenteral treatment at a dosebetween 0.01 to 10 mg/kg bodyweight per injection has the potential tobe safely employed in lactating cows to reduce milk yield and havebeneficial effects if treatment is installed at dry-off in analogy toExamples 2 to 6 of the present invention.

Example 8 Dose/Pharmacodynamics (PD) of Canagliflozin after a SingleParenteral Injection in Lactating Ruminants

In studies in pregnant or non-pregnant, lactating cows, treatment withcanagliflozin is performed as described in Example 1. I.e. employing adose escalation design the cows receive a single parenteral injectioncontaining canagliflozin in weekly intervals. Urinary glucose andcreatinine, blood glucose and ketone body concentration and milk yieldare measured. Pharmacodynamic data are evaluated as described inExample 1. Thus, it is investigated:

-   -   If the urinary glucose excretion normalized to urinary        creatinine increases in a dose/exposure dependent manner.    -   That, after treatment, the milk yield of the subsequent milking        (PM) decreases in a dose/exposure dependent manner.    -   And also, if blood glucose or ketone body level stay within        normal reference ranges after treatment with all dosages.

Thus, similar to what is described with velagliflozin, also forcanagliflozin it is anticipated that a parenteral treatment at a dosebetween 0.01 to 10 mg/kg bodyweight per injection has the potential tobe safely employed in lactating cows to reduce milk yield and havebeneficial effects if treatment is installed at dry-off in analogy toExamples 2 to 6 of the present invention.

Example 9 Dose/Pharmacodynamics (PD) of Empagliflozin after a SingleParenteral Injection in Lactating Ruminants

In studies in pregnant or non-pregnant, lactating cows, treatment withempagliflozin is performed as described in Example 1. I.e. employing adose escalation design the cows receive a single parenteral injectioncontaining empagliflozin in weekly intervals. Urinary glucose andcreatinine, blood glucose and ketone body concentration and milk yieldare measured. Pharmacodynamic data are evaluated as described inExample 1. Thus, it is investigated:

-   -   If the urinary glucose excretion normalized to urinary        creatinine increases in a dose/exposure dependent manner.    -   That, after treatment, the milk yield of the subsequent milking        (PM) decreases in a dose/exposure dependent manner.    -   And also, if blood glucose or ketone body level stay within        normal reference ranges after treatment with all dosages.

Thus, similar to what is described with velagliflozin, also forempagliflozin it is anticipated that a parenteral treatment at a dosebetween 0.01 to 10 mg/kg bodyweight per injection has the potential tobe safely employed in lactating cows to reduce milk yield and havebeneficial effects if treatment is installed at dry-off in analogy toExamples 2 to 6 of the present invention.

Example 10 Dose/Pharmacodynamics (PD) of Ertugliflozin after a SingleParenteral Injection in Lactating Ruminants

In studies in pregnant or non-pregnant, lactating cows, treatment withertugliflozin is performed as described in Example 1. I.e. employing adose escalation design the cows receive a single parenteral injectioncontaining ertugliflozin in weekly intervals. Urinary glucose andcreatinine, blood glucose and ketone body concentration and milk yieldare measured. Pharmacodynamic data are evaluated as described inExample 1. Thus, it is investigated:

-   -   If the urinary glucose excretion normalized to urinary        creatinine increases in a dose/exposure dependent manner.    -   That, after treatment, the milk yield of the subsequent milking        (PM) decreases in a dose/exposure dependent manner.    -   And also, if blood glucose or ketone body level stay within        normal reference ranges after treatment with all dosages.

Thus, similar to what is described with velagliflozin, also forertugliflozin it is anticipated that a parenteral treatment at a dosebetween 0.01 to 10 mg/kg bodyweight per injection has the potential tobe safely employed in lactating cows to reduce milk yield and havebeneficial effects if treatment is installed at dry-off in analogy toExamples 2 to 6 of the present invention.

Example 11 Effects on Milk Composition and Involution Marker—Ex Vivo/InVitro Assessment

The direct effects of SGLT2 inhibition on the bovine mammary gland arestudied in isolated perfused bovine udders as well as in (primary)bovine mammary epithelial cells (MECs).

The beneficial effects on the bovine mammary gland for dry-off are showne.g. in the milk like secretion of perfused udders and/or thesupernatant in MEC cultures—the reduction of lactose and/ortriglycerides are measured. Also, the reduction of markers of milkproduction like beta-casein is quantified, e.g. by determining theprotein content in western blots of cell lysates.

In addition, the expression of involution marker are assessed. Theexposure of perfused bovine udders and/or bovine MECs with at least oneSGLT2 inhibitor according to the present invention influences apoptosisand/or autophagy. These effects are measured, e.g. by quantifying theexpression of markers like transforming growth factor-beta1 and/orsequestosome-1 (also known as p62).

Example 12 Dose/Pharmacodynamics (PD) of Velagliflozin after a SingleAdministration in Lactating Laboratory Animals

In studies in lactating laboratory animals, such as dogs, cats, rats,mice and/or rabbits, treatment with velagliflozin is performed similaras described in Example 1. I.e. employing a dose escalation design theanimals receive a single parenteral injection or, alternatively, oraldosages containing velagliflozin in weekly intervals. Urinary glucoseand creatinine, blood glucose and ketone body concentration and milkyield are measured. In laboratory animals, the milk yield is measuredusing a weigh-suckle-weigh method. Briefly, the mother is separated fromher pups for e.g. 3 h. Then the pups are weighed, allowed to suckle fore.g. 1 h, and are weighed again. This procedure may be repeated severaltimes per day, e.g. the day before and the day of treatment withvelagliflozin.

Pharmacodynamic read outs investigated are e.g.:

-   -   If the urinary glucose excretion normalized to urinary        creatinine increases in a dose/exposure dependent manner.    -   That, after treatment, the milk yield of the subsequent milking        decreases in a dose/exposure dependent manner.    -   And also, if blood glucose or ketone body level stay within        normal reference ranges after treatment with all dosages.

These readings are compared between, before, or after treatment withvelagliflozin, or between animals that are treated with velagliflozincompared to others, that receive no treatment or placebo treatment.

The dose depended reduction of milk secretion of velagliflozin in cows(see Example 1) and laboratory animals indicate that SGLT2 inhibitors,like velagliflozin, but also others can successfully treat any conditionof an animal (preferably ruminants, dogs, cats, horses, pigs) that isassociated with an unwanted lactation—e.g. dry-off in dairy ruminants(Example 1), pseudopregnancy/galactorrhea in animals (Example 17). Butalso, if for other reasons it is required that whelping is to bediscontinued abruptly, the treatment with at least one SGLT2 inhibitoraccording to the present invention is anticipated to reduce the milksecretion and in addition successfully reduce and/or prevent associatedclinical signs—e.g. mammary engorgement, pain, milk leakage and/ormastitis.

Example 13 Dose/Pharmacodynamics (PD) of Dapagliflozin after a SingleAdministration in Lactating Laboratory Animals

In studies in lactating laboratory animals, such as dogs, cats, rats,mice and/or rabbits, treatment with dapagliflozin is performed similaras described in Example 1. I.e. employing a dose escalation design theanimals receive a single parenteral injection or, alternatively, oraldosages containing dapagliflozin in weekly intervals. Urinary glucoseand creatinine, blood glucose and ketone body concentration and milkyield are measured. In laboratory animals, the milk yield is measuredusing a weigh-suckle-weigh method. Briefly, the mother is separated fromher pups for e.g. 3 h. Then the pups are weighed, allowed to suckle fore.g. 1 h, and are weighed again. This procedure may be repeated severaltimes per day, e.g. the day before and the day of treatment withdapagliflozin. Pharmacodynamic read outs investigated are e.g.:

-   -   If the urinary glucose excretion normalized to urinary        creatinine increases in a dose/exposure dependent manner.    -   That, after treatment, the milk yield of the subsequent milking        decreases in a dose/exposure dependent manner.    -   And also, if blood glucose or ketone body level stay within        normal reference ranges after treatment with all dosages.

These readings are compared between, before, or after treatment withdapagliflozin, or between animals that are treated with dapagliflozincompared to others, that receive no treatment or placebo treatment.

Example 14 Dose/Pharmacodynamics (PD) of Canagliflozin after a SingleAdministration in Lactating Laboratory Animals

In studies in lactating laboratory animals, such as dogs, cats, rats,mice and/or rabbits, treatment with canagliflozin is performed similaras described in Example 1. I.e. employing a dose escalation design theanimals receive a single parenteral injection or, alternatively, oraldosages containing canagliflozin in weekly intervals. Urinary glucoseand creatinine, blood glucose and ketone body concentration and milkyield are measured. In laboratory animals, the milk yield is measuredusing a weigh-suckle-weigh method. Briefly, the mother is separated fromher pups for e.g. 3 h. Then the pups are weighed, allowed to suckle fore.g. 1 h, and are weighed again. This procedure may be repeated severaltimes per day, e.g. the day before and the day of treatment withcanagliflozin. Pharmacodynamic read outs investigated are e.g.:

-   -   If the urinary glucose excretion normalized to urinary        creatinine increases in a dose/exposure dependent manner.    -   That, after treatment, the milk yield of the subsequent milking        decreases in a dose/exposure dependent manner.    -   And also, if blood glucose or ketone body level stay within        normal reference ranges after treatment with all dosages.

These readings are compared between, before, or after treatment withcanagliflozin, or between animals that are treated with canagliflozincompared to others, that receive no treatment or placebo treatment.

Example 15 Dose/Pharmacodynamics (PD) of Empagliflozin after a SingleAdministration in Lactating Laboratory Animals

In studies in lactating laboratory animals, such as dogs, cats, rats,mice and/or rabbits, treatment with empagliflozin is performed similaras described in Example 1. I.e. employing a dose escalation design theanimals receive a single parenteral injection or, alternatively, oraldosages containing empagliflozin in weekly intervals. Urinary glucoseand creatinine, blood glucose and ketone body concentration and milkyield are measured. In laboratory animals, the milk yield is measuredusing a weigh-suckle-weigh method. Briefly, the mother is separated fromher pups for e.g. 3 h. Then the pups are weighed, allowed to suckle fore.g. 1 h, and are weighed again. This procedure may be repeated severaltimes per day, e.g. the day before and the day of treatment withempagliflozin. Pharmacodynamic read outs investigated are e.g.:

-   -   If the urinary glucose excretion normalized to urinary        creatinine increases in a dose/exposure dependent manner.    -   That, after treatment, the milk yield of the subsequent milking        decreases in a dose/exposure dependent manner.    -   And also, if blood glucose or ketone body level stay within        normal reference ranges after treatment with all dosages.

These readings are compared between, before, or after treatment withempagliflozin, or between animals that are treated with empagliflozincompared to others, that receive no treatment or placebo treatment.

Example 16 Dose/Pharmacodynamics (PD) of Ertugliflozin after a SingleAdministration in Lactating Laboratory Animals

In studies in lactating laboratory animals, such as dogs, cats, rats,mice and/or rabbits, treatment with ertugliflozin is performed similaras described in Example 1. I.e. employing a dose escalation design theanimals receive a single parenteral injection or, alternatively, oraldosages containing ertugliflozin in weekly intervals. Urinary glucoseand creatinine, blood glucose and ketone body concentration and milkyield are measured. In laboratory animals, the milk yield is measuredusing a weigh-suckle-weigh method. Briefly, the mother is separated fromher pups for e.g. 3 h. Then the pups are weighed, allowed to suckle fore.g. 1 h, and are weighed again. This procedure may be repeated severaltimes per day, e.g. the day before and the day of treatment withertugliflozin. Pharmacodynamic read outs investigated are e.g.:

-   -   If the urinary glucose excretion normalized to urinary        creatinine increases in a dose/exposure dependent manner.    -   That, after treatment, the milk yield of the subsequent milking        decreases in a dose/exposure dependent manner.    -   And also, if blood glucose or ketone body level stay within        normal reference ranges after treatment with all dosages.

These readings are compared between, before, or after treatment withertugliflozin, or between animals that are treated with ertugliflozincompared to others, that receive no treatment or placebo treatment.

Example 17 Treatment with SGLT2 Inhibitors for the Reduction of MilkSecretion in Cases of Unwanted Lactation Incl. e.g. Galactorrhea and/orPseudopregnancy

The previous examples have described, that the administration of atleast one SGLT2 inhibitor according to the present invention cansuccessfully treat any condition of an animal (preferably ruminant, dog,cat, horse, and/or pig) that is associated with an unwantedlactation—e.g. dry-off in dairy ruminants (Example 1). Also, otherclinical conditions are often associated with an unwanted lactation,mammary engorgement and/or milk leakage. E.g. this is encountered indogs affected by pseudopregnancy and/or galactorrhea.

In affected dogs, SGLT-2 inhibitor, such as velaglifozin, treatment canbe performed as a parenteral administration, preferably s.c. or i.m. oralso by oral administration. The treatment may be a single treatment orrepeated daily treatments e.g. ˜24 h or 48 h apart until the symptomsresolve.

Responses to treatment are evaluated by visual inspection of the mammarygland area—i.e. engorgement and/or milk leakage—and/or manual palpationto evaluate pain and/or evolving intra mammary inflammation. Also, theresolution of additional behavioural symptoms (e.g. depression, weightgain, vomiting, or appetite loss) may be evaluated. The read outs may bereported on owner questionnaires.

REFERENCES

-   (1) Bertulat S et al., J Dairy Sci 2017, 100(4): 3220-3232-   (2) EP 2 349 272-   (3) EP 2 675 527-   (4) Gross J J et al., J Anim Physiol Anim Nutr 2015, 99: 747-756-   (5) Lanctôt S et al., J Dairy Sci 2017, 100(3): 2269-2281-   (6) Maynou G et al., J Dairy Sci 2018, 101(12): 1-12-   (7) US 2004/0258778-   (8) US 2011/0245261-   (9) US 2014/0024670-   (10) U.S. Pat. No. 4,412,993-   (11) U.S. Pat. No. 6,391,849-   (12) U.S. Pat. No. 8,133,916-   (13) U.S. Pat. No. 9,487,557-   (14) U.S. Pat. No. 9,744,158-   (15) WO 2004/113378-   (16) WO 2007/128749-   (17) WO 2009/143020-   (18) WO2014/016381-   (19) WO 2015/173584-   (20) WO 2016/104643-   (21) WO 2017/156632-   (22) WO 2019/121509-   (23) Zhao F Q et al., J. Dairy Sci., 2005, 88: 2738-2748-   (24) Zhao F Q, J Mammary Gland Biol Neoplasia 2014, 19: 3-17

The following clauses are also comprised by the present invention:

-   -   1. Use of at least one SGLT-2 inhibitor in ruminants, preferably        for drying-off of ruminants.    -   2. Method of improving and/or facilitating the drying-off of        ruminants comprising administering to such ruminants at least        one SGLT-2 inhibitor.    -   3. Method of reducing the milk production in pregnant and/or        lactating ruminants comprising administering to such ruminants        at least one SGLT-2 inhibitor.    -   4. Method of decreasing milk accumulation and/or engorgement in        the udder of ruminants comprising administering to such        ruminants at least one SGLT-2 inhibitor.    -   5. Method of decreasing the discomfort associated with udder        engorgement, such as increasing the daily lying time and/or        reduction of stress, of ruminants comprising administering to        such ruminants at least one SGLT-2 inhibitor.    -   6. Method of decreasing milk leakage after drying-off of        ruminants comprising administering to such ruminants at least        one SGLT-2 inhibitor.    -   7. Method of decreasing the incidence of intra-mammary        infections (IMI), preferably mastitis and/or metritis, in        ruminants comprising administering to such ruminants at least        one SGLT-2 inhibitor.    -   8. The use or method according to any one of clauses 1 to 7,        wherein the at least one SGLT-2 inhibitor is administered in a        therapeutically effective amount without exerting any harmful        and/or abortifacient effects on pregnant ruminants and/or        wherein the at least one SGLT-2 inhibitor is administered in a        therapeutically effective amount without exerting any negative        effects on the subsequent reproduction cycle/fertility and milk        yield and/or milk quality in the next lactation.    -   9. The use or method according to clause 8, wherein the at least        one SGLT-2 inhibitor is administered in a therapeutically        effective amount that additionally or alternatively effects a        reduction of the incidence of new intra-mammary infections (IMI)        or mastitis in the first month after start of the next        lactation.    -   10. The use or method according to any one of clauses 1 to 9,        wherein the at least one SGLT-2 inhibitor is selected from the        group consisting of:        -   (1) a glucopyranosyl-substituted benzene derivative of the            formula (1)

-   -   wherein R¹ denotes cyano, Cl or methyl (most preferably cyano);        -   R² denotes H, methyl, methoxy or hydroxy (most preferably H)            and            -   R³ denotes cyclopropyl, hydrogen, fluorine, chlorine,                bromine, iodine, methyl, ethyl, propyl, isopropyl,                butyl, sec-butyl, iso-butyl, tert-butyl,                3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl,                1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl,                1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethinyl,                ethoxy, difluoromethyl, trifluoromethyl,                pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl,                3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl,                3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl,                2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl,                2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl,                2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy,                difluoromethyloxy, trifluoromethyloxy,                2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl,                methlysulfonyl, ethylsulfinyl, ethylsulfonyl,                trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or                (S)-tetrahydrofuran-3-yloxy or cyano;            -   wherein R³ is preferably selected from cyclopropyl,                ethyl, ethinyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or                (S)-tetrahydrofuran-3-yloxy; and most preferably R³ is                cyclopropyl,            -   or a derivative thereof wherein one or more hydroxyl                groups of the β-D-glucopyranosyl group are acylated with                groups selected from (C₁₋₁₈-alkyl)carbonyl,                (C₁₋₁₈-alkyl)oxycarbonyl, phenylcarbonyl and                phenyl-(C₁₋₃-alkyl)-carbonyl;        -   (2) Velagliflozin, represented by formula (2):

-   -   (3) Dapagliflozin, represented by formula (3):

-   -   (4) Canagliflozin, represented by formula (4):

-   -   (5) Empagliflozin, represented by formula (6):

-   -   (6) Luseogliflozin, represented by formula (6):

-   -   (7) Tofogliflozin, represented by formula (7):

-   -   (8) Ipragliflozin, represented by formula (8):

-   -   (9) Ertugliflozin, represented by formula (9):

-   -   (10) Atigliflozin, represented by formula (10):

-   -   (11) Remogliflozin, represented by formula (11):

-   -   (11A) Remogliflozin etabonate, represented by formula (11A):

-   -   (12) a thiophene derivative of the formula (12)

-   -   wherein R denotes methoxy or trifluoromethoxy;        -   (13)            1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene,            represented by formula (13);

-   -   (14) a spiroketal derivative of the formula (14):

-   -   wherein R denotes methoxy, trifluoromethoxy, ethoxy, ethyl,        isopropyl or tert. butyl;        -   (15) a pyrazole-O-glucoside derivative of the formula (15)

-   -   wherein        -   R¹ denotes C₁₋₃-alkoxy,            -   L¹, L² independently of each other denote H or F,            -   R⁶ denotes H, (C₁₋₃-alkyl)carbonyl,                (C₁₋₆-alkyl)oxycarbonyl, phenyloxycarbonyl,                benzyloxycarbonyl or benzylcarbonyl;        -   (16) Sotagliflozin, represented by formula (16):

-   -   (17) Sergliflozin, represented by formula (17):

-   -   (18) a compound represented by formula (18):

-   -   wherein    -   R³ denotes cyclopropyl, hydrogen, fluorine, chlorine, bromine,        iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,        iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl,        cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl,        1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl,        1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl,        trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl,        hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl,        3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl,        2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl,        2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl,        2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy,        trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl,        methylsulfinyl, methlysulfonyl, ethylsulfinyl, ethylsulfonyl,        trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or        (S)-tetrahydrofuran-3-yloxy or cyano, and wherein R³ is        preferably selected from cyclopropyl, ethyl, ethinyl, ethoxy,        (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; and        R³ most preferably is cyclopropyl,        -   or a derivative thereof wherein one or more hydroxyl groups            of the β-D-glucopyranosyl group are acylated with groups            selected from (C₁₋₁₈-alkyl)carbonyl,            (C₁₋₁₈-alkyl)oxycarbonyl, phenylcarbonyl and            phenyl-(C₁₋-alkyl)-carbonyl;        -   (19) Bexagliflozin, represented by formula (19):

-   -   (20) Janagliflozin, represented by formula (20):

-   -   11. The use or method according to any one of clauses 1 to 10,        wherein the ruminants are selected from the group consisting of:        bovine, caprine, ovine; more preferably selected from the group        consisting of: cattle, cows, goats, sheep; even more preferably        selected from the group consisting of: dairy cattle, pregnant        and/or lactating dairy cattle; most preferably selected from the        group consisting of: cows, pregnant and/or lactating cows.    -   12. The use or method according to any one of clauses 1 to 11,        wherein the at least one SGLT-2 inhibitor is administered        orally, parenterally, rectally, intravaginally, intravenously,        subcutaneously or intramuscularly, preferably subcutaneously,        intramuscularly or intravenously.    -   13. The use or method according to any one of clauses 1 to 12,        wherein the at least one SGLT-2 inhibitor is administered at a        dose of 0.01 mg/kg bodyweight to 10 mg/kg bodyweight, preferably        at a dose of 0.01 mg/kg bodyweight to 5 mg/kg bodyweight, more        preferably at a dose of 0.01 mg/kg bodyweight to 3 mg/kg        bodyweight, even more preferably at a dose of 0.03 mg/kg        bodyweight to 3 mg/kg bodyweight, most preferably at a dose of        0.03 mg/kg bodyweight or 0.3 mg/kg bodyweight or 3 mg/kg        bodyweight.    -   14. The use or method according to any one of clauses 1 to 13,        wherein the at least one SGLT-2 inhibitor is administered once,        twice, three-times, four-times, five-times, six-times or daily        for a week, preferably once only at start of drying-off or twice        as two treatments 24 hours or 48 hours apart after last milking.    -   15. The use or method according to any one of clauses 1 to 14,        wherein the at least one SGLT-2 inhibitor is velagliflozin and        velagliflozin is administered as single SGLT-2 inhibitor,        preferably subcutaneously or intramuscularly, once only at start        of drying-off or twice (24 h or 48 h apart) at a dose of 0.03        mg/kg bodyweight to 3 mg/kg bodyweight, preferably at a dose of        0.03 mg/kg bodyweight or 0.3 mg/kg bodyweight or 3 mg/kg        bodyweight.    -   16. The use or method according to any one of clauses 1 to 15,        wherein the at least one SGLT-2 inhibitor is administered        before, after or concomitantly with administering at least one        feed supplement, such as Bovikalc® Dry, to the ruminant and/or        before, after or concomitantly with a reduction in feed offered        to the ruminant.    -   17. The use or method according to clause 16, wherein the feed        supplement comprises one or more acidifying agents selected from        the group consisting of: ammonium chloride, calcium chloride        and/or calcium sulfate, more preferably comprises ammonium        chloride and calcium chloride and calcium sulfate, even more        preferably comprises 5% (w/w) to 15% (w/w) ammonium chloride and        40% (w/w) to 60% (w/w) calcium chloride and 15% (w/w) to 25%        (w/w) calcium sulfate, most preferably comprises 10.4% (w/w)        ammonium chloride and 51.9% (w/w) calcium chloride and 20.1%        (w/w) calcium sulfate.

The invention claimed is:
 1. A method of improving and/or facilitating the drying-off of a non-human mammal, comprising administering to the non-human mammal at least one SGLT2 inhibitor, wherein the at least one SGLT-2 inhibitor is selected from the group consisting of: (1) a glucopyranosyl-substituted benzene derivative of the formula (1)

wherein R¹ denotes cyano, Cl or methyl, R² denotes H, methyl, methoxy or hydroxy and R³ denotes cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C₁₋₁₈-alkyl)carbonyl, (C₁₋₁₈-alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C₁₋₃-alkyl)-carbonyl; (2) Velagliflozin, represented by formula (2):

(3) Dapagliflozin, represented by formula (3):

(4) Canagliflozin, represented by formula (4):

(5) Empagliflozin, represented by formula (5):

(6) Luseogliflozin, represented by formula (6):

(7) Tofogliflozin, represented by formula (7):

(8) Ipragliflozin, represented by formula (8):

(9) Ertugliflozin, represented by formula (9):

(10) Atigliflozin, represented by formula (10):

(11) Remogliflozin, represented by formula (11):

(11A) Remogliflozin etabonate, represented by formula (11A):

(12) a thiophene derivative of the formula (12)

wherein R denotes methoxy or trifluoromethoxy; (13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene, represented by formula (13);

(14) a spiroketal derivative of the formula (14):

wherein R denotes methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert-butyl; (15) a pyrazole-O-glucoside derivative of the formula (15):

wherein R¹ denotes C₁₋₃-alkoxy, L¹, L² independently of each other denote H or F, R⁶ denotes H, (C₁₋₃-alkyl)carbonyl, (C₁₋₆-alkyl)oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl or benzylcarbonyl; (16) Sotagliflozin, represented by formula (16):

(17) Sergliflozin, represented by formula (17):

(18) a compound represented by formula (18):

wherein R³ denotes cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C₁₋₁₈-alkyl)carbonyl, (C₁₋₁₈-alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C₁₋₃-alkyl)-carbonyl; (19) Bexagliflozin, represented by formula (19):

(20) Janagliflozin, represented by formula (20):

(21) Rongliflozin; and (22) Wanpagliflozin.
 2. A method according to claim 1, wherein the at least one SGLT-2 inhibitor is administered in a therapeutically effective amount without exerting any harmful and/or abortifacient effects on a pregnant non-human mammal, and/or wherein the at least one SGLT-2 inhibitor is administered in a therapeutically effective amount without exerting any negative effects on the subsequent reproduction cycle/fertility and milk yield and/or milk quality in the next lactation.
 3. The method according to claim 2, wherein the at least one SGLT-2 inhibitor is administered in a therapeutically effective amount that additionally or alternatively effects a reduction of the incidence of new intra-mammary infections (IMI) or mastitis in the first month after start of the next lactation.
 4. The method according to claim 1, wherein the non-human mammal is selected from the group consisting of: bovine, canine, caprine, equine, feline, lagomorphs, ovine, porcine, and rodent.
 5. The method according to claim 1, wherein the at least one SGLT-2 inhibitor is administered orally, parenterally, rectally, intravaginally, intravenously, subcutaneously or intramuscularly.
 6. The method according to claim 1, wherein the at least one SGLT-2 inhibitor is administered at a dose of 0.01 mg/kg bodyweight to 10 mg/kg bodyweight.
 7. The method according to claim 1, wherein the at least one SGLT-2 inhibitor is administered once, twice, three-times, four-times, five-times, six-times or daily for a week.
 8. The method according to claim 1, wherein the at least one SGLT-2 inhibitor is administered once only at start of drying-off or twice as two treatments 24 hours or 48 hours apart after last milking.
 9. The method according to claim 1, wherein the non-human mammal is a cow, a pregnant cow, and/or a lactating cow.
 10. The method according to claim 1, wherein the at least one SGLT-2 inhibitor comprises Velagliflozin, represented by formula:


11. A method of reducing milk production in a pregnant and/or lactating non-human mammal, comprising administering to the non-human mammal at least one SGLT-2 inhibitor, wherein the at least one SGLT-2 inhibitor is selected from the group consisting of: (1) a glucopyranosyl-substituted benzene derivative of the formula (1)

wherein R¹ denotes cyano, Cl or methyl, R² denotes H, methyl, methoxy or hydroxy and R³ denotes cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C₁₋₁₈-alkyl)carbonyl, (C₁₋₁₈-alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C₁₋₃-alkyl)-carbonyl; (2) Velagliflozin, represented by formula (2):

(3) Dapagliflozin, represented by formula (3):

(4) Canagliflozin, represented by formula (4):

(5) Empagliflozin, represented by formula (5):

(6) Luseogliflozin, represented by formula (6):

(7) Tofogliflozin, represented by formula (7):

(8) Ipragliflozin, represented by formula (8):

(9) Ertugliflozin, represented by formula (9):

(10) Atigliflozin, represented by formula (10):

(11) Remogliflozin, represented by formula (11):

(11A) Remogliflozin etabonate, represented by formula (11A):

(12) a thiophene derivative of the formula (12)

wherein R denotes methoxy or trifluoromethoxy; (13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene, represented by formula (13);

(14) a spiroketal derivative of the formula (14):

wherein R denotes methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert-butyl; (15) a pyrazole-O-glucoside derivative of the formula (15):

wherein R¹ denotes C₁₋₃-alkoxy, L¹, L² independently of each other denote H or F, R⁶ denotes H, (C₁₋₃-alkyl)carbonyl, (C₁₋₆-alkyl)oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl or benzylcarbonyl; (16) Sotagliflozin, represented by formula (16):

(17) Sergliflozin, represented by formula (17):

(18) a compound represented by formula (18):

wherein R³ denotes cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C₁₋₁₈-alkyl)carbonyl, (C₁₋₁₈-alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C₁₋₃-alkyl)-carbonyl; (19) Bexagliflozin, represented by formula (19):

(20) Janagliflozin, represented by formula (20):

(21) Rongliflozin; and (22) Wanpagliflozin.
 12. A method of decreasing milk accumulation and/or engorgement in the udder and/or mammary gland of a non-human mammal, comprising administering to the non-human mammal at least one SGLT-2 inhibitor, wherein the at least one SGLT-2 inhibitor is selected from the group consisting of: (1) a glucopyranosyl-substituted benzene derivative of the formula (1)

wherein R¹ denotes cyano, Cl or methyl, R² denotes H, methyl, methoxy or hydroxy and R³ denotes cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C₁₋₁₈-alkyl)carbonyl, (C₁₋₁₈-alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C₁₋₃-alkyl)-carbonyl; (2) Velagliflozin, represented by formula (2):

(3) Dapagliflozin, represented by formula (3):

(4) Canagliflozin, represented by formula (4):

(5) Empagliflozin, represented by formula (5):

(6) Luseogliflozin, represented by formula (6):

(7) Tofogliflozin, represented by formula (7):

(8) Ipragliflozin, represented by formula (8):

(9) Ertugliflozin, represented by formula (9):

(10) Atigliflozin, represented by formula (10):

(11) Remogliflozin, represented by formula (11):

(11A) Remogliflozin etabonate, represented by formula (11A):

(12) a thiophene derivative of the formula (12)

wherein R denotes methoxy or trifluoromethoxy; (13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene, represented by formula (13);

(14) a spiroketal derivative of the formula (14):

wherein R denotes methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert-butyl; (15) a pyrazole-O-glucoside derivative of the formula (15):

wherein R¹ denotes C₁₋₃-alkoxy, L¹, L² independently of each other denote H or F, R⁶ denotes H, (C₁₋₃-alkyl)carbonyl, (C₁₋₆-alkyl)oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl or benzylcarbonyl: (16) Sotagliflozin, represented by formula (16):

(17) Sergliflozin, represented by formula (17):

(18) a compound represented by formula (18):

wherein R³ denotes cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C₁₋₁₈-alkyl)carbonyl, (C₁₋₁₈-alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C₁₋₃-alkyl)-carbonyl; (19) Bexagliflozin, represented by formula (19):

(20) Janagliflozin, represented by formula (20):

(21) Rongliflozin; and (22) Wanpagliflozin.
 13. The method according to claim 12, wherein the at least one SGLT-2 inhibitor comprises Velagliflozin, represented by formula:


14. A method of decreasing the discomfort associated with udder engorgement of a non-human mammal, comprising administering to the non-human mammal at least one SGLT-2 inhibitor.
 15. A method of decreasing milk leakage after drying-off of a non-human mammal, comprising administering to the non-human mammal at least one SGLT-2 inhibitor.
 16. A method of decreasing an incidence of intra-mammary infections (IMI) in a non-human mammal, comprising administering to the non-human mammal at least one SGLT-2 inhibitor.
 17. The method according to any one of claims 14, wherein the at least one SGLT-2 inhibitor is selected from the group consisting of: (1) a glucopyranosyl-substituted benzene derivative of the formula (1)

wherein R¹ denotes cyano, Cl or methyl; R² denotes H, methyl, methoxy or hydroxy and R³ denotes cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C₁₋₁₈-alkyl)carbonyl, (C₁₋₁₈-alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C₁₋₃-alkyl)-carbonyl; (2) Velagliflozin, represented by formula (2):

(3) Dapagliflozin, represented by formula (3):

(4) Canagliflozin, represented by formula (4):

(5) Empagliflozin, represented by formula (5):

(6) Luseogliflozin, represented by formula (6):

(7) Tofogliflozin represented by formula (7):

(8) Ipragliflozin, represented by formula (8):

(9) Ertugliflozin, represented by formula (9):

(10) Atigliflozin, represented by formula (10):

(11) Remogliflozin represented by formula (11):

(11A) Remogliflozin etabonate, represented by formula (11A):

(12) a thiophene derivative of the formula (12)

wherein R denotes methoxy or trifluoromethoxy; (13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene, represented by formula (13);

(14) a spiroketal derivative of the formula (14):

wherein R denotes methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert-butyl; (15) a pyrazole-O-glucoside derivative of the formula (15):

wherein R¹ denotes C₁₋₃-alkoxy, L¹, L² independently of each other denote H or F, R⁶ denotes H, (C₁₋₃-alkyl)carbonyl, (C₁₋₆-alkyl)oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl or benzylcarbonyl; (16) Sotagliflozin, represented by formula (16):

(17) Sergliflozin, represented by formula (17):

(18) a compound represented by formula (18):

wherein R³ denotes cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C₁₋₁₈-alkyl)carbonyl, (C₁₋₁₈-alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C₁₋₃-alkyl)-carbonyl; (19) Bexagliflozin, represented by formula (19):

(20) Janagliflozin, represented by formula (20):

(21) Rongliflozin; and (22) Wanpagliflozin.
 18. The method according to claim 14, wherein the method of decreasing the discomfort associated with udder engorgement of a non-human mammal is increasing the daily lying time and/or reduction of stress.
 19. The method according to claim 16, wherein the intra-mammary infections (IMI) are mastitis and/or metritis.
 20. A method of improving and/or facilitating the drying-off of a non-human mammal, comprising administering to the non-human mammal velagliflozin as a single SGLT-2 inhibitor, wherein velagliflozin is administered subcutaneously or intramuscularly, once only at start of drying-off or twice (24 h or 48 h apart) at a dose of 0.01 mg/kg bodyweight to 10 mg/kg bodyweight.
 21. The method according to claim 20, wherein the at least one SGLT-2 inhibitor is administered before, after or concomitantly with administering at least one feed supplement to the non-human mammal and/or before, after or concomitantly with a reduction in feed offered to the non-human mammal.
 22. The method according to claim 21, wherein the feed supplement comprises one or more acidifying agents selected from the group consisting of: ammonium chloride, calcium chloride and calcium sulfate.
 23. The method according to claim 22, wherein the feed supplement comprises 5% (w/w) to 15% (w/w) ammonium chloride, 40% (w/w) to 60% (w/w) calcium chloride and 15% (w/w) to 25% (w/w) calcium sulfate.
 24. The method according to claim 22, wherein the feed supplement comprises 10.4% (w/w) ammonium chloride, 51.9% (w/w) calcium chloride and 20.1% (w/w) calcium sulfate.
 25. The method according to claim 20, wherein the non-human mammal is a cow, a pregnant cow, and/or a lactating cow. 